Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5E2Z4G)

• DOT Name: Homeobox expressed in ES cells 1 (HESX1)
• Synonyms: Homeobox protein ANF; hAnf
• Gene Name: HESX1
• Related Disease:
  Ataxia-telangiectasia
  Cardiac disease
  Congenital isolated adrenocorticotropic hormone deficiency
  Hypogonadotropic hypogonadism 7 with or without anosmia
  Obesity
  Periventricular nodular heterotopia
  Pituitary gland disorder
  Pituitary hormone deficiency, combined, 1
  Septooptic dysplasia
  Systemic lupus erythematosus
  Combined pituitary hormone deficiencies, genetic form
  Hypothyroidism due to deficient transcription factors involved in pituitary development or function
  Kallmann syndrome
  Pituitary stalk interruption syndrome
  Hypothyroidism
  PEHO syndrome
  Pituitary dwarfism
  Rheumatoid arthritis
  X-linked adrenal hypoplasia congenita
• UniProt ID: HESX1_HUMAN
• PDB ID: 2K40
• Pfam ID: PF00046
• Sequence:
  MSPSLQEGAQLGENKPSTCSFSIERILGLDQKKDCVPLMKPHRPWADTCSSSGKDGNLCL
  HVPNPPSGISFPSVVDHPMPEERASKYENYFSASERLSLKRELSWYRGRRPRTAFTQNQI
  EVLENVFRVNCYPGIDIREDLAQKLNLEEDRIQIWFQNRRAKLKRSHRESQFLMAKKNFN
  TNLLE
• Function: Required for the normal development of the forebrain, eyes and other anterior structures such as the olfactory placodes and pituitary gland. Possible transcriptional repressor. Binds to the palindromic PIII sequence, 5'-AGCTTGAGTCTAATTGAATTAACTGTAC-3'. HESX1 and PROP1 bind as heterodimers on this palindromic site, and, in vitro, HESX1 can antagonize PROP1 activation.
• KEGG Pathway: Sig.ling pathways regulating pluripotency of stem cells (hsa04550)

Molecular Interaction Atlas (MIA) of This DOT

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Ataxia-telangiectasia	DISP3EVR	Strong	Biomarker	[1]
Cardiac disease	DISVO1I5	Strong	Biomarker	[2]
Congenital isolated adrenocorticotropic hormone deficiency	DISYMJJV	Strong	Genetic Variation	[3]
Hypogonadotropic hypogonadism 7 with or without anosmia	DISPBWEU	Strong	Genetic Variation	[4]
Obesity	DIS47Y1K	Strong	Biomarker	[5]
Periventricular nodular heterotopia	DISU3ZRI	Strong	Genetic Variation	[6]
Pituitary gland disorder	DIS7XB48	Strong	Biomarker	[7]
Pituitary hormone deficiency, combined, 1	DISVFM4T	Strong	GermlineCausalMutation	[8]
Septooptic dysplasia	DISXYR1H	Strong	Autosomal recessive	[9]
Systemic lupus erythematosus	DISI1SZ7	Strong	Biomarker	[1]
Combined pituitary hormone deficiencies, genetic form	DISW6YL6	Supportive	Autosomal dominant	[8]
Hypothyroidism due to deficient transcription factors involved in pituitary development or function	DISCAAEX	Supportive	Autosomal dominant	[10]
Kallmann syndrome	DISO3HDG	Supportive	Autosomal dominant	[4]
Pituitary stalk interruption syndrome	DISGSN5T	Supportive	Autosomal dominant	[11]
Hypothyroidism	DISR0H6D	Limited	Biomarker	[12]
PEHO syndrome	DISPO5IP	Limited	Genetic Variation	[13]
Pituitary dwarfism	DISI019B	Limited	Genetic Variation	[14]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[15]
X-linked adrenal hypoplasia congenita	DISNMXY8	Limited	Altered Expression	[16]

11 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Homeobox expressed in ES cells 1 (HESX1).	[17]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Homeobox expressed in ES cells 1 (HESX1).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Homeobox expressed in ES cells 1 (HESX1).	[19]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Homeobox expressed in ES cells 1 (HESX1).	[20]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Homeobox expressed in ES cells 1 (HESX1).	[21]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Homeobox expressed in ES cells 1 (HESX1).	[19]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Homeobox expressed in ES cells 1 (HESX1).	[22]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Homeobox expressed in ES cells 1 (HESX1).	[22]
Belinostat	DM6OC53	Phase 2	Belinostat decreases the expression of Homeobox expressed in ES cells 1 (HESX1).	[22]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Homeobox expressed in ES cells 1 (HESX1).	[24]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Homeobox expressed in ES cells 1 (HESX1).	[25]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Homeobox expressed in ES cells 1 (HESX1).	[23]

References

• [1] HIGH PREVALENCE OF HYPOTHYROIDISM IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS WITHOUT AN INCREASE IN CIRCULATING ANTI-THYROID ANTIBODIES.Endocr Pract. 2017 Nov;23(11):1304-1310. doi: 10.4158/EP161664.OR. Epub 2017 Aug 17.
• [2] Cardiac natriuretic peptides gene expression and secretion in inflammation.J Investig Med. 2009 Jan;57(1):29-32. doi: 10.2310/JIM.0b013e3181948b37.
• [3] Hormonal, pituitary magnetic resonance, LHX4 and HESX1 evaluation in patients with hypopituitarism and ectopic posterior pituitary lobe.Clin Endocrinol (Oxf). 2007 Jan;66(1):95-102. doi: 10.1111/j.1365-2265.2006.02692.x.
• [4] Identification of HESX1 mutations in Kallmann syndrome. Fertil Steril. 2013 Jun;99(7):1831-7. doi: 10.1016/j.fertnstert.2013.01.149. Epub 2013 Mar 1.
• [5] Hypogonadotropic hypogonadism.Semin Reprod Med. 2002 Nov;20(4):327-38. doi: 10.1055/s-2002-36707.
• [6] Ectopic posterior pituitary lobe and periventricular heterotopia: cerebral malformations with the same underlying mechanism?.AJNR Am J Neuroradiol. 2002 Oct;23(9):1475-81.
• [7] Pituitary Stalk Interruption Syndrome: From Clinical Findings to Pathogenesis.J Neuroendocrinol. 2017 Jan;29(1). doi: 10.1111/jne.12451.
• [8] A homozygous mutation in HESX1 is associated with evolving hypopituitarism due to impaired repressor-corepressor interaction. J Clin Invest. 2003 Oct;112(8):1192-201. doi: 10.1172/JCI18589.
• [9] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [10] Congenital hypothyroidism. Orphanet J Rare Dis. 2010 Jun 10;5:17. doi: 10.1186/1750-1172-5-17.
• [11] Pituitary stalk interruption syndrome in 83 patients: novel HESX1 mutation and severe hormonal prognosis in malformative forms. Eur J Endocrinol. 2011 Apr;164(4):457-65. doi: 10.1530/EJE-10-0892. Epub 2011 Jan 26.
• [12] DNA testing in patients with GH deficiency at the time of transition.Growth Horm IGF Res. 2003 Aug;13 Suppl A:S122-9. doi: 10.1016/s1096-6374(03)00068-6.
• [13] PEHO Syndrome May Represent Phenotypic Expansion at the Severe End of the Early-Onset Encephalopathies.Pediatr Neurol. 2016 Jul;60:83-7. doi: 10.1016/j.pediatrneurol.2016.03.011. Epub 2016 Apr 9.
• [14] HESX1 mutations in patients with congenital hypopituitarism: variable phenotypes with the same genotype.Clin Endocrinol (Oxf). 2016 Sep;85(3):408-14. doi: 10.1111/cen.13067. Epub 2016 Apr 28.
• [15] Occurrence of autoimmune diseases and relationship of autoantibody expression with HLA phenotypes in multicase rheumatoid arthritis families.Scand J Rheumatol. 1993;22(4):152-7. doi: 10.3109/03009749309099263.
• [16] Advances in the molecular genetics of hypogonadotropic hypogonadism.J Pediatr Endocrinol Metab. 2001 Jan;14(1):3-15. doi: 10.1515/jpem.2001.14.1.3.
• [17] Design principles of concentration-dependent transcriptome deviations in drug-exposed differentiating stem cells. Chem Res Toxicol. 2014 Mar 17;27(3):408-20.
• [18] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [19] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [20] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [21] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [22] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [23] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [24] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [25] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.